A fundamental observation in oncology is that the rate of malignancies increases significantly as a function of age suggesting a potential mechanistic link between the cellular process governing longevity and the development of cancers. In this regard, the genes that play a critical role in longevity (or aging) have recently been characterized in Saccharomyces cerevisiae and C. elegans and the human homologs of these genes are referred to as the Sirtuin gene family. Thus, we hypothesized that the sirtuin genes might function as fidelity genes and loss sirtuin function, which might occur during aging, would create cellular environment permissive for age related illness including carcinogenesis. To address this idea we constructed mice four years ago that have the mitochondrial localized SIRT3 protein genetically deleted. Our laboratory has recently shown that these mice develop estrogen and progesterone receptor (ER/PR) positive mammary tumors that are a subtype of cancer commonly observed in older women. The results of these experiments suggest that SIRT3 is the first identified genomic expressed, mitochondrial localized tumor suppressor (TS) and also suggests a genetic relationship between a mitochondrial aging gene and a cellular environment or phenotype permissive for development of mammary tumors. It has also been shown that intracellular reactive oxygen species (ROS), as well as the mitochondrial superoxide dismutase gene (MnSOD) - the primary superoxide scavenging protein - play a role in aging and carcinogenesis. In this regard, our preliminary results demonstrated altered superoxide in our SIRT3 knockout mice. Thus, we hypothesize that agents thought to prevent the cellular effects of aging and the accumulation of intracellular ROS, such as CR, will be prevent tumors in the SIRT3 knockout mice. In addition, use a series of immunohistochemical staining to characterize the pathological, histology, and redox changes in the murine ductal cells to begin to identify the potential underlying in vivo mechanism of carcinogenic permissive phenotype observed in the SIRT3 knockout mice. PUBLIC HEALTH RELEVANCE: The overarching theme of this proposal is based on one of the fundamental observations in oncology showing that the rate of malignancies increases significantly with age. Recently, it was shown that the Sirtuin gene family may determine aging (longevity). Thus, we hypothesize a genetic and biochemical relationship between the mitochondrial sirtuin, SIRT3, metabolism, and ER/PR positive breast cancers.